Sustained release implant and method for preparing same

ABSTRACT

A mixture comprising a dispersion of a water-diffusible solid in a solution of a non-aqueous solvent and a substantially water-insoluble polymer is formed. The non-aqueous solvent is removed from the mixture to substantially dry the mixture, and the substantially dry mixture is comminuted to form particles. A plurality of the particles are formed under pressure to produce a pellet suitable for use as a sustained release implant device.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a sustained release pellet suitable foruse as an implant in a living being.

2. Description of the Background Art

In many therapeutic, medical and veterinary programs, it is oftendesirable and/or necessary to provide for the slow release of abeneficial agent to a living being at a controlled rate over a prolongedperiod of time.

There have been various approaches in attempting to provide a sustainedrelease device which could release a beneficial agent, such as a drug orhormone, at a controlled rate. One method used is to mix the agent witha carrier material that is gradually broken down by body fluids, theagent being released as the carrier disintegrates. Waxes, oils, fats andsoluble polymers are some materials that have been used as the carriersin these sytems.

Methods for producing implants wherein a protein is the beneficial agent(active ingredient) and a polymer is the carrier or matrix material, areknown in the art. These methods involve either the casting of adispersion of a protein in a polymer solution followed by slow removalof solvent from the solution at low temperature (e.g., overnight at -60°C.), or by compression molding of a dry mixture of a protein and polymerparticles. The former method produces implants with low density (e.g.,0.75 g/cc) and poor mechanical properties, while the latter methodrequires high polymer loading with concomitant low protein loading.

There remains a need in the art for a process capable of yieldingimplants with high protein loading good mechanical properties, and whichis capable of being carried out at room temperatures.

SUMMARY OF THE INVENTION

In accordance with the present invention, a method for preparing apellet containing a water-insoluble polymer and a water-diffusible solidincludes the steps of forming a mixture comprising a dispersion of awater-diffusible solid in a solution of a non-aqueous solvent and awater-insoluble polymer. The non-aqueous solvent is removed from themixture to substantially dry the mixture. The substantially dry mixturethen is comminuted to form substantially dry particles and a pluralityof the particles are formed under pressure into a pellet.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

A pellet containing a water-insoluble polymer and a water-diffusiblesolid according to the present invention is administered to a livingbeing, i.e., human or animal, by implantation of the pellet into bodytissues, insertion of the device into a body cavity, or oral ingestionby the living being.

The polymer material, with which a diffusible solid is dispersed,becomes a matrix through which the diffusible solid, which is abeneficial agent, must diffuse before entering the fluid medium.Diffusion of the beneficial agent occurs as body fluids graduallypenetrate the pellet. The polymer is substantially insoluble in andimpermeable to the fluid medium as well as substantially impermeable tothe diffusible solid.

The diffusible solid to be used in a pellet according to the presentinvention may be any agent which produces a beneficial effect in thebody of a living being. Beneficial effect is defined as aphysiologically or pharmacologically useful effect in the body of aliving being either at a site in close proximity to the point of releaseof the agent, or at a site removed from the release point. Some examplesof beneficial agents include hormones, hypnotics, sedatives,antibiotics, tranquilizers, anti-convulsants, muscle relaxants,anti-bloat agents, antipyretics, anti-inflammatories, analgesics, localanethetics, muscle contractants, steroids, anthelmintics,anti-microbials, diuretics, neoplastics, hypoglycemics, amino acids,opthalmic agents, nutritional supplements and vitamins.

According to one embodiment, a biologically active protein, such as ahormone, is utilized as the beneficial, water-diffusible solid agent. Ina particularly preferred embodiment, the beneficial agent is an animalgrowth hormone, such as bovine, porcine or ovine growth hormone.

The polymers used in the matrix with the beneficial agent arebio-compatible with body tissues and body fluids of the living being andsubstantially insoluble in these body fluids. Body fluids include waterand aqueous-based fluid, such as tissue juices, tear fluids, and thelike. The term matrix denotes a carrier polymeric phase comprising apolymer that is bio-compatible and sufficiently resistant to chemicaland/or physical attack by the environment of use such that the matricesremain substantially intact throughout the prolonged period of time thebeneficial agent is released from the pellet. Polymeric matrices usefulaccording to the present invention are bio-compatible in the environmentof use and substantially insoluble in and substantially impermeable tothe passage of the beneficial agent with which the polymer is mixed.Typical polymeric materials for forming matrices include the naturallyoccurring and synthetic commercially available polymers such aspartially and completely hydrolyzed alkylene-vinyl acetate copolymers;including hydroxylated and unhydroxylated ethylene-vinyl acetatecopolymers, polycaprolactone, semi-permeable polyglycolic or polylacticacid and derivatives thereof and derivatives of polystyrene such aspoly(sodium styrenesulfonate) and poly(vinylbenzyltrimethylammoniumchloride), acyl-substituted cellulose acetates and alkyl derivativesthereof; unplasticized cellulose acetate, bio-compatible cellulosenitrate, cellulose diacetate, cellulose triacetate, agar acetate,amylose triacetate, beta-glucan acetate, beta-glucan triacetate,cellulose acetate, acetaldehyde dimethyl acetate, cellulose acetateethyl carbamate, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate, cellulose acetatedimethaminoacetate, cellulose acetate ethyl carbonate, cellulose acetatechloroacetate, cellulose acetate ethyl oxatate, cellulose acetate methylsulfonate, cellulose acetate butyl sulfonate, cellulose acetatepropionate, cellulose acetate butyl sulfonate, cellulose acetatepropionate, cellulose acetate p-toluene sulfonate, triacetate of locustgum bean, cellulose acetate with acetylated hydroxy-ethyl cellulose,plasticized or unplasticized polyvinyl chloride, homo-and copolymers ofpolyvinyl acetate, polymers of acrylic acid and methacrylic acid,polyvinyl alkyl ethers, polyvinyl fluoride, polycarbonates, polymericepoxides, copolymers of an alkylene oxide and alkyl glycidyl ether,polyurethanes, silicone; polyamide; polysulphones, styrene acrylonitratecopolymers; cross-linked poly(ethylene oxide), poly(alkylenes);poly(vinyl) imidazole), poly(esters); and chlorosulphonated polyolefins.These polymeric materials are listed as mere typical examples, and arenot to be construed in a limiting sense.

According to one embodiment, a substantially water-insoluble polymer isselected from the group consisting of ethylene-vinyl acetate copolymer,polycaprolactone or polylactic acid.

To prepare the matrix of polymeric material and diffusible solid, thediffusible solid (beneficial agent) is dispersed in a solution of thepolymeric material and a non-aqueous solvent. The solvents used in thepreparation of pellets according to the invention will depend upon thepolymeric material chosen as well as the beneficial agent employed.According to this embodiment, the polymeric material is soluble in thesolvent and the beneficial agent is insoluble in the solvent. Methylenedichloride has been found to be a suitable solvent for forming asolution of ethylene/vinyl acetate copolymer, polycaprolactone orpolylactic acid, and therein dispersing a protein such as lysozyme orgrowth hormone as the water-diffusible solid.

The solvent is removed from the dispersion of the water-diffusible solidin the polymer solution by, for example, evaporation under vacuum atroom temperature (e.g., for 30 minutes).

The substantially dry mixture from which the solvent has been removed byvacuum evaporation then is comminuted (ground) in, for example, ablender or grinder for approximately 2 minutes to yield fine particles.The resulting particles comprise water-diffusible solid coated withwater-insoluble polymer.

A plurality of the particles are formed under pressure to produce apellet. This can be accomplished by pressing or tableting the particlesin a conventional tableting machine to give high density-high loadingimplants. Any residual amounts of solvent can be removed under vacuum.

A pellet according to the present invention can be formed from a mixtureof about 25 to 70 parts by weight of the beneficial agent and from about75 to 25 parts by weight of polymer. Advantageously the mixture willcontain about 40 to 60 parts by weight beneficial agent and from about60 to 40 parts by weight polymer.

The process of the present invention can be carried out at roomtemperature to yield a substantially homogeneous implant with highloading and good mechanical properties for subsequent operations such asmembrane coating, wax coating, and the like, as is practiced in theimplant art.

The invention is further illustrated by the following examples, whichare not intended to be limiting.

EXAMPLE I Lysozyme/Ethylene-Vinyl Acetate Copolymer (EVA) Implant

3.0 g of 250 um Lysozyme was mixed with 5.16 g of 10.3% EVA/CH₂ Cl₂solution in a vial. After thorough mixing, the methylene dichloride (CH₂Cl₂) was evaporated. The solid mixture was ground in a Janke-Kunklegrinder for approximately 2 minutes. Tablets were made on the Stokestableting machine. These were used for further studies includingdissolution rate, polymer coating, and the like.

EXAMPLE 2 Lysozyme/Polycaprolactone (PCL)

Lyophilized lysozyme was sieved with an ultrasonic sifter to giveparticles of size -60 +140 mesh. One gram of the lysozyme was dispersedin 10 ml of methylene dichloride (CH₂ Cl₂) containing 0.111 g ofpolycaprolactone (mol wt.: 31,000 daltons). The slurry was kept in avortex stirrer for 2 minutes and in an ultrasonic water bath for 16minutes. The slurry was then transferred to a 100-ml round bottom flaskwith 20 ml of CH₂ Cl₂. The CH₂ Cl₂ was evaporated in a rotary evaporatorat room temperature and about 125 mm of pressure. The lysozyme, coatedwith the polymer, was further dried at room temperature and about 25 mmof pressure. One hundred mg of this solid was placed in the Stokesmachine and pellets were made from a setting of 8.2 mm (lengths) and 4mm (diameter). However, the final pellets were 9 mm (l) and 4 mm (d).The pellets were firm and were used for further studies.

EXAMPLE 3 Bovine Growth Hormone (bGH)/Polylactic Acid (PLA) Implants

Bovine growth hormone (bGH), 800 mg, was suspended in the methylenedichloride (CH₂ Cl₂) solution (about 1.7 g) containing 141 mg ofpolylactic acid (mol wt. of (15,600). Evaporation of solvent gave bGHcoated with PLA which was dried under vacuum (about 125 mm) at roomtemperature. Tablets were then made from 106 mg samples using the Stokesmachine. The length of the cylinder was 7.2-7.5 mm and the diameter was4.0 mm. These were coated with PLA and PCL and studied for releaseprofile.

EXAMPLE 4 Bovine Growth Hormone (bGH)/Polycaprolactone (PCL) Implants

In an experiment similar to Example 3, 800 mg of bGH was dispersed inmethylene dichloride (CH₂ Cl₂) solution (about 1.7 g) containing 141 mgof PCL. Evaporation of the solvent gave bGH coated with PCL. Tabletswere made as described above and used for further studies.

What is claimed is:
 1. A method for preparing a pellet containingeffective amount of a substantially water-insoluble polymer and a growthhormone, the method comprising:(a) forming a mixture comprising adispersion of a growth hormone in a solution of a non-aqueous solventand a substantially water-insoluble polymer: (b) removing thenon-aqueous solvent from the mixture to substantially dry the mixture;(c) comminuting the substantially dry mixture to form particles; and (d)forming a plurality of the particles under pressure to produce a pellet.2. The method of claim 1 wherein the water-insoluble polymers isselected from the group consisting of partially and completelyhydrolyzed alkylene-vinyl acetate copolymers; including hydroxylated andunhydroxylated ethylene-vinyl acetate copolymers, polycaprolactone,semi-permeable polyglycolic or polylactic acid and derivatives thereofand derivatives of polystyrene such as poly(sodium styrenesulfonate) andpoly(vinylbenzyltrimethylammonium chloride), acyl-substituted celluloseacetates and alkyl derivatives thereof; unplasticized cellulose acetate,bio-compatible cellulose nitrate, cellulose diacetate, cellulosetriacetate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, cellulose acetate, acetaldehyde dimethyl acetate,cellulose acetate ethyl carbamate, cellulose acetate phthalate,cellulose acetate methyl carbamate, cellulose acetate succinate,cellulose acetate dimethaminoacetate, cellulose acetate ethyl carbonate,cellulose acetate chloroacetate, cellulose acetate ethyl oxatate,cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate,cellulose acetate propionate, cellulose acetate butyl sulfonate,cellulose acetate propionate, cellulose acetate p-toluene sulfonate,triacetate of locust gum bean, cellulose acetate with acetylatedhydroxy-ethyl cellulose, plasticized or unplasticized polyvinylchloride, homo-and copolymers of polyvinyl acetate, polymers of acrylicacid and methacrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride,polycarbonates, polymeric epoxides, copolymers of an alkylene oxide andalkyl glycidyl ether, polyurethanes, silicone; polyamide; polysulphones,styrene acrylonitrate copolymers; cross-linked poly(ethylene oxide),poly(alkylenes); poly(vinyl) imidazole), poly(esters); andchlorosulphonated polyolefins.
 3. The method of claim 1 wherein thehormone comprises from about 25% to about 75% by weight of said pellet.4. The method of claim 3 wherein said water-insoluble polymer isethylene-vinyl acetate copolymer, polycaprolactone or polylactic acid.5. The method of claim 4 wherein said non-aqueous solvent is methylenedichloride.
 6. The method of claim 1 wherein said hormone is bovinegrowth hormone, porcine growth hormone or ovine growth hormone.
 7. Themethod of claim 3 wherein said growth hormone is bovine growth hormone,porcine growth hormone or ovine growth hormone.
 8. The method of claim 2wherein said hormone is bovine growth hormone, porcine growth hormone orovine growth hormone.
 9. The method of claim 5 wherein said growthhormone is bovine growth hormone, porcine growth hormone or ovine growthhormone.
 10. The method of claim 9 further including the step ofremoving residual non-aqueous solvent from the pellet after forming thepellet.
 11. A pellet produced according to the method of claim
 1. 12. Amethod for preparing a pellet containing effective amounts of asubstantially water-insoluble polymer and a growth hormone, the methodcomprising:(a) forming a mixture by dispersing a growth hormone selectedfrom the group consisting of bovine, porcine, or ovine growth hormone ina solution of a non-aqueous solvent and a ethylene-vinyl acetatecopolymer; (b) removing the non-aqueous solvent from the mixture tosubstantially dry the mixture; (c) comminuting the substantially drymixture to form particles; and (d) compression molding a plurality ofthe particles to form a pellet
 13. The method of claim 12 wherein thesolvent is methylene dichloride.
 14. The method of claim 12 wherein thegrowth hormone comprises form about 25% to about 75% by weight of saidpellet.
 15. The method of claim 12 further comprising the step ofremoving residual solvent from the pellet.
 16. A pellet producedaccording to the method of claim 12.